In a new study, researchers from the Ludwig Cancer Research Center have developed a new type of immunotherapy that uses a two-pronged approach to attack solid tumors to enhance the immune system's ability to target and eliminate cancer cells. The relevant research results were published in the Journal of Clinical Investigation. The paper is titled "Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells."
The new study focuses on an immunotherapy called "adoptive cell transfer (ACT)", which involves extracting T cells from the patient, enhancing their anti-cancer ability, expanding the T cells in culture, and re-infusing them into the patient.
"While T-cell therapy has been a huge success in treating certain blood cancers, solid tumors present more complex challenges due to immunosuppressive mechanisms in the tumor microenvironment," said Melita Irving, a researcher at the Ludwig Cancer Research Center who led the study. "T cells alone may not be enough, which is why we are exploring ways to improve T-cell effectiveness by integrating other immune-enhancing strategies."
In the new study, Irving and her team engineered T cells to secrete CV1, a high-affinity version of the human protein SiRPα. SiRPα normally interacts with CD47, a protein found on the surface of healthy cells that delivers a "don't eat me" signal to prevent macrophages from engulfing them. However, many cancer cells exploit this system and overexpress CD47 to avoid being engulfed.
Figure 1. Harness macrophages by combining CV1-coengineered TCR-T cells with targeted antibodies to direct phagocytosis against tumor cells. (Stefanidis E, et al., 2024)
"The innate immune system, especially macrophages that can engulf tumor cells, is critical to our immune defense against cancer," Irving explained. T cells belong to another branch of the immune system, the adaptive immune system.
The CV1 decoy that Irving's team had previously developed binds to CD47 with high affinity, effectively inhibiting this "don't eat me" signal. This was expected to increase the recognizability of cancer cells, making them more susceptible to attack by macrophages, which would in turn make them targets for these engineered T cells. In addition to secreting CV1, these engineered T cells also express affinity-optimized T cell receptors (TCRs).
However, Irving's team ran into an unexpected problem. The CV1 they engineered their T cells to secrete included an Fc tail, which is typically found on the tail end of antibody molecules and is a tag that attracts macrophage attack. Because the tag was now coated on the T cells that secreted the engineered CV1, this led to a full-scale attack by macrophages on these therapeutic T cells, resulting in exhaustion of the T cells delivered to the mice.
To change this situation, Evangelos Stefanidis, the first author of the paper and a doctoral student in Irving's team, modified T cells to express only CV1 without the Fc tail. In this way, the modified T cells will not be targeted by human macrophages.
In addition, combining these CV1-producing T cells with cancer-targeted antibodies such as avelumab and cetuximab can further enhance the ability of macrophages to engulf tumor cells. This is because these antibodies, which target the immunosuppressive PD-L1 molecule and the growth-promoting epidermal growth factor receptor (EGFR), respectively, have active Fc tails that can attract macrophages to specifically attack tumor cells. Irving's team also observed that treating mice with these antibodies effectively changed the tumor microenvironment and supported immune attacks.
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"By removing the Fc tail, we can shield T cells from attack by human macrophages, and by combining these engineered T cells with clinical antibodies containing active Fc tails, we can enhance macrophage phagocytosis of tumor cells in a targeted manner," Irving explained.
The findings may also help explain why clinical trials of the antibody drug magrolimab have faced significant challenges, including poor patient responses and infections. Like the CV1 decoy, magrolimab blocks the CD47 "don't eat me" signal on the surface of tumor cells, thereby promoting the immune system to destroy tumor cells. However, if, like the CV1 decoy with the Fc tail, its blocking effect is not exclusively targeted to cancer cells, it could cause destruction of healthy tissue.
"Mololimab also has the potential to target immune cells, including T cells, for phagocytosis," Irving said. "Our combination therapy strategy helps direct phagocytosis specifically to tumor cells while protecting our engineered T cells. Our findings also highlight the complexity of cancer treatment and the importance of a nuanced approach to immunotherapy."
Reference
Stefanidis E, et al. Combining SiRPα decoy-coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells. The Journal of Clinical Investigation, 2024, 134(11).